DESCRIPTION

FASLODEX® (fulvestrant) injection for intramuscular
administration is an estrogen receptor antagonist. The chemical name is
7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)-
triene3,17-beta-diol. The molecular formula is C32H47F5O3S
and its structural formula is:

Fulvestrant is a white powder with a molecular weight of
606.77. The solution for injection is a clear, colorless to yellow, viscous
liquid.

Each injection contains as inactive ingredients: 10% w/v
Alcohol, USP, 10% w/v Benzyl Alcohol, NF, and 15% w/v Benzyl Benzoate, USP, as
co-solvents, and made up to 100% w/v with Castor Oil, USP as a co-solvent and
release rate modifier.

DOSAGE AND ADMINISTRATION

Recommended Dose

Monotherapy

The recommended dose is 500 mg to be administered
intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per
injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and
once monthly thereafter [see Clinical Studies].

Combination Therapy With Palbociclib

When FASLODEX is used in combination with palbociclib,
the recommended dose is 500 mg to be administered intramuscularly into the
buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL
injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter.
The recommended dose of palbociclib is a 125 mg capsule taken orally once daily
for 21 consecutive days followed by 7 days off treatment to comprise a complete
cycle of 28 days. Palbociclib should be taken with food. Please refer to the
full prescribing information of palbociclib.

Dose Modification

Monotherapy

Hepatic Impairment

A dose of 250 mg is recommended for patients with
moderate hepatic impairment (Child-Pugh class B) to be administered
intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5
mL injection on days 1, 15, 29 and once monthly thereafter.

Combination Therapy With Palbociclib

When FASLODEX is used in combination with palbociclib,
refer to monotherapy dose modification instructions for FASLODEX. Refer to the
full prescribing information of palbociclib for its dose modification,
management of toxicities, and for use with concomitant medication.

Administration Technique

Administer the injection according to the local
guidelines for performing large volume intramuscular injections.

NOTE: Due to the proximity of the underlying sciatic
nerve, caution should be taken if administering FASLODEX at the dorsogluteal
injection site [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

The proper method of administration of FASLODEX for
intramuscular use is described in the following instructions.

For each syringe:

1. Remove glass syringe barrel from tray and check that
it is not damaged.

2. Remove perforated patient record label from syringe.

3. Inspect drug product in glass syringe for any visible
particulate matter or discoloration prior to use. Discard if particulate matter
or discoloration is present.

4. Peel open the safety needle (SafetyGlide™) outer
packaging.

5. Hold the syringe upright on the ribbed part (C). With
the other hand, take hold of the cap (A) and carefully tilt cap back and forth
(DO NOT TWIST CAP) until the cap disconnects for removal (see Figure 1).

Figure 1

6. Pull the cap (A) off in a straight upward direction.
DO NOT TOUCH THE STERILE SYRINGE TIP (Luer-Lok) (B) (see Figure 2).

Figure 2

7. Attach the safety needle to the syringe tip
(Luer-Lok). Twist needle until firmly seated (see Figure 3). Confirm that the
needle is locked to the Luer connector before moving or tilting the syringe out
of the vertical plane to avoid spillage of syringe contents.

Figure 3

For Administration:

8. Pull shield straight off needle to avoid damaging
needle point.

9. Remove needle sheath.

10. Expel excess gas from the syringe (a small gas bubble
may remain).

11. Administer intramuscularly slowly (1-2
minutes/injection) into the buttock (gluteal area). For user convenience, the
needle 'bevel up' position is orientated to the lever arm, as shown in Figure
4.

Figure 4

12. After injection, immediately activate the lever arm
to deploy the needle shielding by applying a single-finger stroke to the
activation assisted lever arm to push the lever arm completely forward. Listen
for a click. Confirm that the needle shielding has completely covered the
needle (see Figure 5). NOTE: Activate away from self and others.

Figure 5

13. Discard the empty single use syringe into an approved
sharps collector in accordance with applicable regulations and institutional
policy.

14. Repeat steps 1 through 13 for second syringe.

How To Use FASLODEX

For the 2 x 5 mL syringe package, the contents of both
syringes must be injected to receive the 500 mg recommended dose.

Important Administration Information

To help avoid HIV (AIDS), HBV (Hepatitis), and other
infectious diseases due to accidental needlesticks, contaminated needles should
not be recapped or removed, unless there is no alternative or that such action
is required by a specific medical procedure. Hands must remain behind the
needle at all times during use and disposal.

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, the adverse reaction rates observed cannot be directly
compared to rates in other trials and may not reflect the rates observed in
clinical practice.

Monotherapy

Comparison Of FASLODEX 500 mg And FASLODEX 250 mg

The following adverse reactions (ARs) were calculated
based on the safety analysis of CONFIRM comparing the administration of
FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg
intramuscularly once a month. The most frequently reported adverse reactions in
the fulvestrant 500 mg group were injection site pain (11.6% of patients),
nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently
reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6%
of patients), back pain (10.7% of patients) and injection site pain (9.1% of
patients).

Table 1 lists adverse reactions reported with an incidence
of 5% or greater, regardless of assessed causality, from CONFIRM.

In the pooled safety population (N=1127) from clinical
trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of
≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in
>15% of patients receiving FASLODEX. Grade 3-4 increases were observed in
1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT,
AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison Of FASLODEX 500 mg And Anastrozole 1 mg
(FALCON)

The safety of FASLODEX 500 mg versus anastrozole 1 mg was
evaluated in FALCON. The data described below reflect exposure to FASLODEX in
228 out of 460 patients with HR-positive advanced breast cancer in
postmenopausal women not previously treated with endocrine therapy who received
at least one (1) dose of treatment in FALCON.

*In the FALCON, post-baseline increases of ≥1 CTC
grade in either AST, ALT, or alkaline phosphatase were observed in >10% of
patients receiving FASLODEX. Grade 3-4 increases were observed in 1%-3% of
patients.

Injection site reactions with mild transient pain and
inflammation were seen with FASLODEX and occurred in 7% of patients given the
single 5 mL injection (Study 0020) and in 27% of patients given the 2 x 2.5 mL
injections (Study 0021) in the two clinical trials that compared FASLODEX 250
mg and anastrozole 1 mg.

Table 4 lists adverse reactions reported with an
incidence of 5% or greater, regardless of assessed causality, from the two
controlled clinical trials comparing the administration of FASLODEX 250 mg
intramuscularly once a month with anastrozole 1 mg orally once a day.

1 Including more severe injection site related
sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All patients
on FASLODEX received injections, but only those anastrozole patients who were
in Study 0021 received placebo injections.

Combination Therapy With Palbociclib

The safety of FASLODEX 500 mg plus palbociclib 125 mg/day
versus FASLODEX plus placebo was evaluated in PALOMA-3. The data described
below reflect exposure to FASLODEX plus palbociclib in 345 out of 517 patients
with HR-positive, HER2-negative advanced or metastatic breast cancer who
received at least 1 dose of treatment in PALOMA-3.

No dose reduction was allowed for FASLODEX in PALOMA-3.
Dose reductions of palbociclib due to an adverse reaction of any grade occurred
in 36% of patients receiving FASLODEX plus palbociclib.

Postmarketing Experience

For FASLODEX 250 mg, other adverse reactions reported as
drug-related and seen infrequently (<1%) include thromboembolic phenomena,
myalgia, vertigo, leukopenia, and hypersensitivity reactions including
angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%),
mainly in patients during the first 6 weeks after changing from existing
hormonal therapy to treatment with FASLODEX. If bleeding persists, further
evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis,
and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS

There are no known drug-drug interactions. Although,
fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with
ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose
adjustment is not needed in patients co-prescribed CYP 3A4 inhibitors or inducers
[see CLINICAL PHARMACOLOGY].

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Bleeding

Because FASLODEX is administered intramuscularly, it
should be used with caution in patients with bleeding diatheses,
thrombocytopenia, or anticoagulant use.

Increased Exposure In Patients With Hepatic Impairment

The safety and pharmacokinetics of FASLODEX were
evaluated in a study in seven subjects with moderate hepatic impairment
(Child-Pugh class B) and seven subjects with normal hepatic function. Exposure
was increased in patients with moderate hepatic impairment, therefore a dose of
250 mg is recommended [see DOSAGE AND ADMINISTRATION].

FASLODEX has not been studied in patients with severe
hepatic impairment (Child-Pugh class C) [see Use In Specific Populations].

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism
of action, FASLODEX can cause fetal harm when administered to a pregnant woman.
In animal reproduction studies, administration of fulvestrant to pregnant rats
and rabbits during organogenesis resulted in embryo-fetal toxicity at daily
doses that are significantly less than the maximum recommended human dose.
Advise pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during treatment with
FASLODEX and for one year after the last dose [see Use In Specific
Populations and CLINICAL PHARMACOLOGY].

Immunoassay Measurement Of Serum Estradiol

Due to structural similarity of fulvestrant and
estradiol, FASLODEX can interfere with estradiol measurement by immunoassay,
resulting in falsely elevated estradiol levels.

Patient Counseling Information

Monotherapy

Risk Of Bleeding

Because FASLODEX is administered intramuscularly, it
should be used with caution in patients with bleeding disorders, decreased
platelet count, or in patients receiving anticoagulants (for example, warfarin)
[see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential
risk to a fetus and to use effective contraception during treatment with
FASLODEX and for one year after the last dose. Advise females to inform their
healthcare provider of a known or suspected pregnancy [see WARNINGS AND
PRECAUTIONS and Use In Specific Populations].

Lactation

Advise women not to breast-feed during treatment with
FASLODEX and for one year after the last dose [see Use In Specific
Populations].

Combination Therapy With Palbociclib

See palbociclib full prescribing information for Patient
Counseling Information.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenesis studies were conducted in rats
and mice. Positive findings were observed in both species. Rats were treated at
intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15
days.

These doses correspond to 0.9-, 1.5-, and 3-fold (in
females) and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure [AUC0-30
days] achieved in women receiving the recommended dose of 500 mg/month. An
increased incidence of benignovarian granulosa cell tumors and testicular
Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males
dosed at 15 mg/rat/30 days, respectively. Mice were treated at oral doses of 0,
20, 150 and 500 mg/kg/day. These doses correspond to 0, 0.8, 8.4 and 18fold (in
females) and 0.8-, 7.1- and 11.9-fold (in males), the systemic exposure (AUC0-30
days) achieved in women receiving the recommended dose of 500 mg/month. There
was an increased incidence of sex cordstromal tumors (both benign and
malignant) in the ovary of mice at doses of 150 and 500 mg/kg/day. Induction of
such tumors is consistent with the pharmacology-related endocrine feedback
alterations in gonadotropin levels caused by an antiestrogen.

Fulvestrant was not mutagenic or clastogenic in multiple in
vitro tests with and without the addition of a mammalian liver metabolic
activation factor (bacterial mutation assay in strains of Salmonella
typhimurium and Escherichia coli, in vitro cytogenetics study in human
lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus
test in rat).

In female rats, fulvestrant administered at doses
≥0.01 mg/kg/day (0.6% the human recommended dose based on body surface
area [BSA in mg/m²]), for 2 weeks prior to and for 1 week following mating,
caused a reduction in fertility and embryonic survival. No adverse effects on
female fertility and embryonic survival were evident in female animals dosed at
0.001 mg/kg/day (0.06% the human dose based on BSA in mg/m²). Restoration of
female fertility to values similar to controls was evident following a 29-day
withdrawal period after dosing at 2 mg/kg/day (equivalent to the human dose
based on BSA in mg/m²). The effects of fulvestrant on the fertility of female
rats appear to be consistent with its antiestrogenic activity. The potential
effects of fulvestrant on the fertility of male animals were not studied but,
in a 6-month toxicology study, male rats treated with intramuscular doses of 15
mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a
loss of spermatozoa from the seminiferous tubules, seminiferous tubular
atrophy, and degenerative changes in the epididymides. Changes in the testes
and epididymides had not recovered 20 weeks after cessation of dosing. These
fulvestrant doses correspond to 1.3-, 1.2- and 3.5-fold the systemic exposure
[AUC0-30 days] achieved in women receiving the recommended dose of 500
mg/month.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism
of action, FASLODEX can cause fetal harm when administered to a pregnant woman [see
CLINICAL PHARMACOLOGY]. There are no available data in pregnant women to
inform the drug-associated risk. In animal reproduction studies, administration
of fulvestrant to pregnant rats and rabbits during organogenesis caused
embryo-fetal toxicity, including skeletal malformations and fetal loss, at
daily doses that were 6% and 30% of the maximum recommended human dose based on
mg/m², respectively [see Data]. Advise pregnant women of the potential
risk to a fetus.

The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.

Data

Animal Data

Administration of fulvestrant to rats prior to and up to
implantation caused embryonic loss at daily doses that were 0.6% of the daily
maximum recommended human dose based on mg/m². When fulvestrant was
administered to pregnant rats during the period of organogenesis, intramuscular
doses ≥0.1 mg/kg/day (6% of the human recommended dose based on mg/m²)
caused effects on embryo-fetal development consistent with its antiestrogenic
activity. Fulvestrant caused an increased incidence of fetal abnormalities in
rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human
dose based on mg/m²) and non-ossification of the odontoid and ventraltubercle
of the first cervicalvertebra at doses ≥0.1 mg/kg/day. Fulvestrant
administered at 2 mg/kg/day caused fetal loss.

When administered to pregnant rabbits during the period
of organogenesis, fulvestrant caused pregnancy loss at an intramuscular dose of
1 mg/kg/day (equivalent to the human dose based on mg/m²). Further, at 0.25
mg/kg/day (30% the human dose based on mg/m²), fulvestrant caused increases in
placental weight and post-implantation loss in rabbits. Fulvestrant was
associated with an increased incidence of fetal variations in rabbits
(backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at
0.25 mg/kg/day; 30% the human dose based on mg/m²) when administered during the
period of organogenesis.

Lactation

Risk Summary

There is no information regarding the presence of
fulvestrant in human milk, nor of its effects on milk production or breast-fed
infant. Fulvestrant can be detected in rat milk [see Data]. Because of
the potential for serious adverse reactions in breast-fed infants from
FASLODEX, advise a lactating woman not to breast-feed during treatment with
FASLODEX and for one year after the final dose.

Data

Levels of fulvestrant were approximately 12-fold higher
in milk than in plasma after exposure of lactating rats to a dose of 2 mg/kg.
Drug exposure in rodent pups from fulvestrant-treated lactating dams was
estimated as 10% of the administered dose. In a study in rats of fulvestrant at
10 mg/kg given twice or 15 mg/kg given once (less than the recommended human dose
based on mg/m²) during lactation, offspring survival was slightly reduced.

Females and Males Of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of
reproductive potential within seven days prior to initiating FASLODEX.

Contraception

Females

FASLODEX can cause fetal harm when administered to a
pregnant woman [see Use In Specific Populations]. Advise females of
reproductive potential to use effective contraception during treatment and for
one year after the last dose.

Infertility

Based on animal studies, FASLODEX may impair fertility in
females and males of reproductive potential. The effects of fulvestrant on
fertility were reversible in female rats [see Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness in pediatric patients have not
been established. A multi-center, single-arm, open-label, study of fulvestrant
was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with
progressive precocious puberty (PPP). The median age at informed consent was 6
years old (range: 1 to 8).

The first 10 patients initially received fulvestrant 2
mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2
mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4
mg/kg from study entry.

Baseline measurements for vaginal bleeding days, bone
age, growth velocity, and Tanner staging for at least 6 months prior to study
entry were provided retrospectively by the parent, guardian or local
consultant. All measurements during the study period were collected
prospectively. Patients' baseline characteristics included the following: a
mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age
advancement (change in bone age in years divided by change in chronological age
in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.

Twenty-nine of 30 patients completed the 12-month study
period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23
patients with baseline vaginal bleeding experienced a complete cessation of
vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone
age advancement during the 12-month study period compared to baseline (mean
change = -0.9 [95% CI: -1.4, -0.4]); and a reduction in mean growth velocity
Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI: -2.7,
0.4]). There were no clinically meaningful changes in median Tanner stage
(breast or pubic), mean uterine volume, or mean ovarian volume, or predicted
adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on
bone mineral density in children has not been studied and is not known.

Eight patients (27%) experienced adverse reactions that
were considered possibly related to FASLODEX. These included injection site
reactions (inflammation, pain, hematoma, pruritus, rash), abdominal pain,
contusion, tachycardia, hot flash, extremity pain, and vomiting. Nine (30.0%)
patients reported an SAE, none of which were considered related to FASLODEX. No
patients discontinued study treatment due to an AE and no patients died.

Pharmacokinetics

The pharmacokinetics of fulvestrant was characterized
using a population pharmacokinetic analysis with sparse samples per patient
obtained from 30 female pediatric patients aged 1 to 8 years with PPP
associated with MAS. Pharmacokinetic data from 294 postmenopausal women with
breast cancer who received 125 or 250 mg monthly dosing regimen were also
included in the analysis.

Geriatric Use

For FASLODEX 250 mg, when tumor response was considered
by age, objective responses were seen in 22% and 24% of patients under 65 years
of age and in 11% and 16% of patients 65 years of age and older, who were
treated with FASLODEX in Study 0021 and Study 0020, respectively.

Hepatic Impairment

FASLODEX is metabolized primarily in the liver.

The pharmacokinetics of fulvestrant were evaluated after
a single dose of 100 mg in subjects with mild and moderate hepatic impairment
and normal hepatic function (n = 7 subjects/group), using a shorter-acting
intramuscular injection formulation. Subjects with mild hepatic impairment
(Child-Pugh class A) had comparable mean AUC and clearance values to those with
normal hepatic function. In subjects with moderate hepatic impairment
(Child-Pugh class B), the average AUC of fulvestrant increased by 70% compared
to patients with normal hepatic function. AUC was positively correlated with
total bilirubin concentration (p = 0.012). FASLODEX has not been studied in
patients with severe hepatic impairment (Child-Pugh class C).

A dose of FASLODEX 250 mg is recommended in patients with
moderate hepatic impairment (Child-Pugh class B) [see DOSAGE AND ADMINISTRATION
and WARNINGS AND PRECAUTIONS].

Renal Impairment

Negligible amounts of fulvestrant are eliminated in
urine; therefore, a study in patients with renal impairment was not conducted.
In the advanced breast cancer trials, fulvestrant concentrations in women with
estimated creatinine clearance as low as 30 mL/min were similar to women with
normal creatinine.

Overdosage & Contraindications

OVERDOSE

Human experience of overdose with FASLODEX is limited.
There are isolated reports of overdose with FASLODEX in humans. No adverse
reactions were seen in healthy male and female volunteers who received
intravenous fulvestrant, which resulted in peak plasma concentrations at the
end of the infusion, that were approximately 10 to 15 times those seen after
intramuscular injection. The potential toxicity of fulvestrant at these or
higher concentrations in cancer patients who may have additional comorbidities
is unknown. There is no specific treatment in the event of fulvestrant
overdose, and symptoms of overdose are not established. In the event of an
overdose, healthcare practitioners should follow general supportive measures
and should treat symptomatically.

CONTRAINDICATIONS

FASLODEX is contraindicated in patients with a known
hypersensitivity to the drug or to any of its components. Hypersensitivity
reactions, including urticaria and angioedema, have been reported in
association with FASLODEX [see ADVERSE REACTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Many breast cancers have estrogen receptors (ER) and the
growth of these tumors can be stimulated by estrogen. Fulvestrant is an
estrogen receptor antagonist that binds to the estrogen receptor in a
competitive manner with affinity comparable to that of estradiol and
downregulates the ER protein in human breast cancer cells.

In vitro studies demonstrated that fulvestrant is a
reversible inhibitor of the growth of tamoxifen-resistant, as well as
estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor
studies, fulvestrant delayed the establishment of tumors from xenografts of
human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth
of established MCF-7 xenografts and of tamoxifen-resistant breast tumor
xenografts.

Fulvestrant showed no agonist-type effects in in vivo uterotropic
assays in immature or ovariectomized mice and rats. In in vivo studies in
immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic
action of estradiol. In postmenopausal women, the absence of changes in plasma
concentrations of FSH and LH in response to fulvestrant treatment (250 mg
monthly) suggests no peripheral steroidal effects.

Pharmacodynamics

In a clinical study in postmenopausal women with primary
breast cancer treated with single doses of FASLODEX 15-22 days prior to
surgery, there was evidence of increasing down-regulation of ER with increasing
dose. This was associated with a dose-related decrease in the expression of the
progesterone receptor, an estrogen-regulated protein. These effects on the ER
pathway were also associated with a decrease in Ki67 labeling index, a marker
of cell proliferation.

Pharmacokinetics

Absorption

The single dose and multiple dose PK parameters for the
500 mg dosing regimen with an additional dose (AD) at Day 15 are reported in
Table 7. The additional dose of FASLODEX given two weeks after the initial dose
allows for steady state concentrations to be reached within the first month of
dosing.

Distribution

The apparent volume of distribution at steady state is
approximately 3 to 5 L/kg. This suggests that distribution is largely
extravascular. Fulvestrant is highly (99%) bound to plasma proteins; VLDL, LDL
and HDLlipoprotein fractions appear to be the major binding components. The
role of sex hormone-binding globulin, if any, could not be determined.

Metabolism

Biotransformation and disposition of fulvestrant in
humans have been determined following intramuscular and intravenous
administration of 14C-labeled fulvestrant. Metabolism of fulvestrant
appears to involve combinations of a number of possible biotransformation
pathways analogous to those of endogenous steroids, including oxidation,
aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the
2, 3 and 17 positions of the steroidnucleus, and oxidation of the side chain
sulphoxide. Identified metabolites are either less active or exhibit similar
activity to fulvestrant in antiestrogen models.

Studies using human liver preparations and recombinant
human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450
isoenzyme involved in the oxidation of fulvestrant; however, the relative
contribution of P-450 and non-P-450 routes in vivo is unknown.

Excretion

Fulvestrant was rapidly cleared by the hepatobiliary
route with excretion primarily via the feces (approximately 90%). Renal
elimination was negligible (less than 1%). After an intramuscular injection of
250 mg, the clearance (Mean ± SD) was 690 ± 226 mL/min with an apparent
half-life about 40 days.

Special Populations

Geriatric

In patients with breast cancer, there was no difference
in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).

Gender

Following administration of a single intravenous dose,
there were no pharmacokinetic differences between men and women or between
premenopausal and postmenopausal women. Similarly, there were no differences
between men and postmenopausal women after intramuscular administration.

Race

In the advanced breast cancer treatment trials, the
potential for pharmacokinetic differences due to race have been evaluated in
294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No
differences in fulvestrant plasma pharmacokinetics were observed among these
groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic
Japanese women were similar to those obtained in non-Japanese patients.

Drug-Drug Interactions

There are no known drug-drug interactions. Fulvestrant
does not significantly inhibit any of the major CYP isoenzymes, including CYP
1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of
fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have
no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized by
that enzyme. Although fulvestrant is partly metabolized by CYP 3A4, a clinical
study with rifampin, an inducer of CYP 3A4, showed no effect on the
pharmacokinetics of fulvestrant. Also results from a healthy volunteer study
with ketoconazole, a potent inhibitor of CYP 3A4, indicated that ketoconazole
had no effect on the pharmacokinetics of fulvestrant and dosage adjustment is
not necessary in patients co-prescribed CYP 3A4 inhibitors or inducers [see DRUG
INTERACTIONS]. Data from a clinical trial in patients with breast cancer
showed that there was no clinically relevant drug interaction between
fulvestrant and palbociclib when the two drugs were co-administered.

Clinical Studies

The efficacy of FASLODEX 500 mg versus FASLODEX 250 mg
was compared in CONFIRM. The efficacy of FASLODEX 250 mg was compared to 1 mg
anastrozole in Studies 0020 and 0021. The efficacy of FASLODEX 500 mg was
compared to 1 mg anastrozole in FALCON. The efficacy of FASLODEX 500 mg in
combination with palbociclib 125 mg was compared to FASLODEX 500 mg plus
placebo in PALOMA-3.

Monotherapy

Comparison Of FASLODEX 500 mg And FASLODEX 250 mg
(CONFIRM)

A randomized, double-blind, controlled clinical trial
(CONFIRM, NCT00099437) was completed in 736 postmenopausal women with advanced
breast cancer who had disease recurrence on or after adjuvant endocrine therapy
or progression following endocrine therapy for advanced disease. This trial
compared the efficacy and safety of FASLODEX 500 mg (n=362) with FASLODEX 250
mg (n=374).

FASLODEX 500 mg was administered as two 5 mL injections
each containing FASLODEX 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and
every 28 (+/- 3) days thereafter. FASLODEX 250 mg was administered as two 5 mL
injections (one containing FASLODEX 250 mg/5mL injection plus one placebo
injection), one in each buttock, on Days 1, 15 (2 placebo injections only), 29
and every 28 (+/- 3) days thereafter.

The median age of study participants was 61. All patients
had ER+ advanced breast cancer. Approximately 30% of subjects had no measurable
disease. Approximately 55% of patients had visceral disease.

Results of CONFIRM are summarized in Table 8. The
efficacy of FASLODEX 500 mg was compared to that of FASLODEX 250 mg. Figure 6
shows a Kaplan-Meier plot of the Progression Free Survival (PFS) data after a
minimum follow-up duration of 18 months demonstrating statistically significant
superiority of FASLODEX 500 mg vs. FASLODEX 250 mg. In the initial Overall
Survival (OS) analysis after a minimum follow-up duration of 18 months, there
was no statistically significant difference in OS between the two treatment
groups. After a minimum follow-up duration of 50 months, an updated OS analysis
was performed. Figure 7 shows a Kaplan-Meier plot of the updated OS data.

Table 8: Efficacy Results CONFIRM: Intent-To-Treat
(ITT) Population

Endpoint

Fulvestrant 500 mg
(N=362)

Fulvestrant 250 mg
(N=374)

PFS1

Median (months)

6.5

5.4

Hazard Ratio2 (95% CI3 )

0.80 (0.68-0.94)

p-value

0.006

OS4 Updated Analysis5(% patients who died)

261 (72.1%)

293 (78.3%)

Median OS (months)

26.4

22.3

Hazard Ratio2 (95% CI3)6

0.81 (0.69-0.96)

ORR7 (95% CI3)

13.8% (9.7%, 18.8%) (33/240)

14.6% (10.5%, 19.4%) (38/261)

1 PFS (Progression Free Survival) = the time
between randomization and the earliest of progression or death from any cause.
Minimum follow-up duration of 18 months. 2 Hazard Ratio <1 favors FASLODEX 500 mg. 3 CI=Confidence Interval 4 OS=Overall Survival 5 Minimum follow up duration of 50 months. 6 Not statistically significant as no adjustments were made for
multiplicity. 7 ORR (Objective Response Rate), as defined as number (%) of
patients with complete response or partial response, was analyzed in the
evaluable patients with measureable disease at baseline (fulvestrant 500 mg
N=240; fulvestrant 250 mg N=261). Minimum follow-up duration of 18 months.

A randomized, double-blind, double-dummy, multicenter
study (FALCON, NCT01602380) of FASLODEX 500 mg versus anastrozole 1 mg was
conducted in postmenopausal women with ER-positive and/or PgR-positive,
HER2-negative locally advanced or metastatic breast cancer who had not
previously been treated with any hormonal therapy. A total of 462 patients were
randomized 1:1 to receive administration of FASLODEX 500 mg as an intramuscular
injection on Days 1, 15, 29 and every 28 (+/- 3) days thereafter or daily
administration of 1 mg of anastrozole orally. This study compared the efficacy
and safety of FASLODEX 500 mg and anastrozole 1 mg.

Randomization was stratified by disease setting (locally
advanced or metastatic), use of prior chemotherapy for advanced disease, and
presence or absence of measurable disease.

Patients enrolled in this study had a median age of 63
years (range 36-90). The majority of patients (87%) had metastatic disease at
baseline. Fifty-five percent (55%) of patients had visceral metastasis at
baseline. A total of 17% of patients had received one prior chemotherapy
regimen for advanced disease; 84% of patients had measurable disease. Sites of
metastases were as follows: musculoskeletal 59%, lymph nodes 50%, respiratory
40%, liver (including gall bladder) 18%.

Efficacy of FASLODEX was established by comparison to the
selective aromatase inhibitor anastrozole in two randomized, controlled
clinical trials (one conducted in North America, Study 0021, NCT00635713; the
other predominantly in Europe, Study 0020) in postmenopausal women with locally
advanced or metastatic breast cancer. All patients had progressed after
previous therapy with an antiestrogen or progestin for breast cancer in the
adjuvant or advanced disease setting.

The median age of study participants was 64. 81.6% of
patients had ER+ and/or PgR+ tumors. Patients with ER- /PgR- or unknown tumors
were required to have demonstrated a prior response to endocrine therapy. Sites
of metastases occurred as follows: visceral only 18.2%; viscera – liver involvement
23.0%; lung involvement 28.1%; bone only 19.7%; soft tissue only 5.2%; skin and
soft tissue 18.7%.

In both trials, eligible patients with measurable and/or
evaluable disease were randomized to receive either FASLODEX 250 mg
intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once
a day. All patients were assessed monthly for the first three months and every
three months thereafter. Study 0021 was a double-blind, randomized trial in 400
postmenopausal women. Study 0020 was an open-label, randomized trial conducted
in 451 postmenopausal women. Patients on the FASLODEX arm of Study 0021
received two separate injections (2 X 2.5 mL), whereas FASLODEX patients
received a single injection (1 X 5 mL) in Study 0020. In both trials, patients
were initially randomized to a 125 mg per month dose as well, but interim
analysis showed a very low response rate, and low dose groups were dropped.

Results of the trials, after a minimum follow-up duration
of 14.6 months, are summarized in Table 10. The effectiveness of FASLODEX 250
mg was determined by comparing Objective Response Rate (ORR) and Time to
Progression (TTP) results to anastrozole 1 mg, the active control. The two
studies ruled out (by one-sided 97.7% confidence limit) inferiority of FASLODEX
to anastrozole of 6.3% and 1.4% in terms of ORR. There was no statistically
significant difference in overall survival (OS) between the two treatment
groups after a follow-up duration of 28.2 months in Study 0021 and 24.4 months
in Study 0020.

A total of 521 pre/postmenopausal women were randomized
2:1 to FASLODEX plus palbociclib or FASLODEX plus placebo and stratified by documented
sensitivity to prior hormonal therapy, menopausal status at study entry
(pre/peri versus postmenopausal), and presence of visceral metastases.
Palbociclib was given orally at a dose of 125 mg daily for 21 consecutive days
followed by 7 days off treatment. Fulvestrant 500 mg was administered as two 5
mL injections each containing fulvestrant 250 mg/5mL, one in each buttock, on
Days 1, 15, 29 and every 28 (+/- 3) days thereafter. Pre/perimenopausal women
were enrolled in the study and received the LHRH agonist goserelin for at least
4 weeks prior to and for the duration of PALOMA-3.

Patients continued to receive assigned treatment until
objective disease progression, symptomatic deterioration, unacceptable
toxicity, death, or withdrawal of consent, whichever occurred first. The major
efficacy outcome of the study was investigator-assessed PFS evaluated according
to RECIST 1.1.

Patients enrolled in this study had a median age of 57
years (range 29 to 88). The majority of patients in each treatment arm were
White (74%), all patients had an ECOG PS of 0 or 1, and 80% were
postmenopausal. All patients had received prior systemic therapy and 75% of
patients had received a previous chemotherapy regimen. Twenty-five percent of
patients had received no prior therapy in the metastatic disease setting, 60%
had visceral metastases, and 23% had bone only disease.

The results from the investigator-assessed PFS from
PALOMA-3 are summarized in Table 11 and Figure 9. Consistent results were
observed across patient subgroups of disease site, sensitivity to prior
hormonal therapy and menopausal status. Confirmed overall response rate in
patients with measurable disease as assessed by the investigator was 24.6% in
the FASLODEX plus palbociclib and was 10.9% in the FASLODEX plus placebo arm.
Duration of response was 9.3 months in the FASLODEX plus palbociclib arm
compared with 7.6 months in the FASLODEX plus placebo arm. At the time of final
analysis of PFS, OS data were not mature with 29% of events.

HR-positive advanced breast cancer, who have gone through
menopause and whose disease has progressed after endocrine therapy

HR-positive, HER2-negative advanced breast cancer or
breast cancer that has spread to other parts of the body (metastatic), in
combination with palbociclib in women whose disease has progressed after
endocrine therapy

When FASLODEX is used in combination with palbociclib,
please also see the palbociclib Patient Information.

It is not known if FASLODEX is safe and effective in
children.

It is not known if FASLODEX is safe and effective in
people with severe liver problems.

Who should not receive FASLODEX?

Do not receive FASLODEX if you have had an
allergic reaction to fulvestrant or any of the ingredients in FASLODEX. See the
end of this leaflet for a list of the ingredients in FASLODEX. Symptoms of an
allergic reaction to FASLODEX may include:

Itching or hives

swelling of your face, lips, tongue or throat

trouble breathing

What should I tell my healthcare provider before
receiving FASLODEX?

Before receiving FASLODEX, tell your healthcare
provider about all of your medical conditions, including if you:

have a low level of platelets in your blood or bleed
easily.

have liver problems.

are pregnant or plan to become pregnant. FASLODEX can
harm your unborn baby.

Females who are able to become pregnant should use
effective birth control during treatment with FASLODEX and for one year after
the last dose of FASLODEX.

Tell your healthcare provider right away if you become
pregnant or think you are pregnant during treatment with FASLODEX.

are breastfeeding or plan to breastfeed. It is not known
if FASLODEX passes into your breast milk. Do not breast-feed during your
treatment with FASLODEX and for one year after the final dose of FASLODEX. Talk
to your healthcare provider about the best way to feed your baby during this
time.

Tell your healthcare provider about all the medicines
you take, including prescription and over the counter medicines, vitamins,
and herbal supplements. FASLODEX may affect the way other medicines work, and
other medicines may affect how FASLODEX works.

Especially tell your healthcare provider if you
take a blood thinner medicine.

How will I receive FASLODEX?

Your healthcare provider will give you FASLODEX by
injection into the muscle of each buttock.

Your healthcare provider may change your dose of FASLODEX
if needed.

What are the possible side effects of FASLODEX?

FASLODEX may cause injection site related nerve damage.
Call your healthcare provider if you develop any of the following symptoms in
your legs following a FASLODEX injection:

FASLODEX may cause fertility problems in males and
females. Talk to your healthcare provider if you plan to become pregnant.

Tell your healthcare provider if you have any side effect
that bothers you or that does not go away.

These are not all of the possible side effects with
FASLODEX. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about
side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use
of FASLODEX

Medicines are sometimes prescribed for purposes other
than those listed in a Patient Information leaflet. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or
healthcare provider for information about FASLODEX that is written for health
professionals.